Antibacterial agents

ABSTRACT

Napthyridine derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed.

FIELD OF THE INVENTION

This application is a national stacie entry of PCT/US06/02537, filed 24 Jan. 2006, which claims the benefit of U.S. Provisional Application No. 60/646,879, filed 25 Jan. 2005.

BACKGROUND OF THE INVENTION

The emergence of pathogens resistant to known antibiotic therapy is becoming a serious global healthcare problem (Chu, et al., (1996) J. Med. Chem., 39: 3853-3874). Thus, there is a need to discover new broad spectrum antibiotics useful in combating multidrug-resistant organisms. Importantly, it has now been discovered that certain compounds have antibacterial activity, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in humans. WO125227, WO0240474, WO0207572, WO04024712, WO04024713, WO9937635, WO0021948, WO0021952, WO0043383, WO0078748, WO0107433, WO0107432, WO0208224, WO0224684, WO0250061, WO0250040, WO0256882, WO0296907, WO03087098, WO03010138, WO03064431, WO03064421, WO04002992, and WO0400249 disclose quinoline and/or naphthyridine derivatives having antibacterial activity.

SUMMARY OF THE INVENTION

This invention comprises compounds of the formula (I), as described hereinafter, which are useful in the treatment of bacterial infections. This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. This invention is also processes for the preparation of compounds of formula (I), as well as processes for the preparation of intermediates useful in the synthesis of compounds of formula (I). This invention is also novel intermediates useful in the preparation of antibacterial agents. This invention is also a method of treating bacterial infections in mammals, particularly in humans.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof:

wherein:

Z₁, Z₃, and Z₄ are independently N or CR^(1a);

Z₂, Z₅, and Z₆ are each CR^(1a);

R₁ and R^(1a) are independently at each occurrence hydrogen; cyano; halogen; hydroxy; (C₁₋₆)alkoxy unsubstituted or substituted by (C₁₋₆)alkoxy, hydroxy, amino, piperidyl, guanidino or amidino any of which is unsubstituted or N-substituted by one or two (C₁₋₆)alkyl, acyl, (C₁₋₆)alkylsulphonyl, CONH₂, hydroxy, (C₁₋₆)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide; arylsulphonyl; arylsulphoxide; or an amino, piperidyl, guanidino or amidino group unsubstituted or N-substituted by one or two (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups; or R₁ and R^(1a) of Z₂ together form ethylenedioxy;

W₁, W₂, and W₃ are each CR₃R₄;

B is CR₆R₇ or C═O;

R₃, R₄, R₆, and R₇ are independently at each occurrence hydrogen; thiol; (C₁₋₆)alkylthio; halogen; trifluoromethyl; azido; (C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenylcarbonyl; (C₂₋₆)alkenyloxycarbonyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; hydroxy; NR^(1b)R^(1b′); (C₁₋₆)alkylsulphonyl; C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonyl wherein the amino group is optionally and independently substituted by hydrogen, (C₁₋₆)alkyl, (C₂₋₆)alkenyl or aralkyl;

R₅ is hydrogen; halogen; hydroxyl; or (C₁₋₆)alkyl;

R₂ and R₈ are independently hydrogen, trifluoromethyl; (C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl; aryl; aralkyl; (C₃₋₈)cycloalkyl; heterocyclyl; or heterocyclylalkyl;

R^(1b) and R^(1b′) are independently at each occurrence hydrogen; (C₁₋₆)alkyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; or together with the nitrogen that they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring are optionally substituted with from 1 to 3 substituents selected from halogen, hydroxy; cyano; nitro; (C₁₋₆)alkyl; and aryl);

R₉ is UR₁₀;

U is CH₂; C(═O); or SO₂;

R₁₀ is a substituted or unsubstituted bicyclic, carbocyclic, or heterocyclic ring system (A):

containing up to four heteroatoms in each ring in which at least one of rings (a) and (b) is aromatic;

X¹ is C or N when part of an aromatic ring or CR₁₁ when part of a non aromatic ring;

X² is N, NR₁₂, O, S(O)_(n), CO or CR₁₁ when part of an aromatic or non-aromatic ring or may in addition be CR₁₃R₁₄ when part of a non aromatic ring;

n is independently at each occurrence 0, 1, or 2;

X³ and X⁵ are independently N or C;

Y¹ is a 0 to 4 atom linker group each atom of which is independently selected from N, NR₁₂, O, S(O)_(n), CO and CR₁₁ when part of an aromatic or non-aromatic ring or may additionally be CR₁₃R₁₄ when part of a non aromatic ring,

Y² is a 2 to 6 atom linker group, each atom of Y² being independently selected from N, NR₁₂, O, S(O)_(n), CO and CR₁₁ when part of an aromatic or non-aromatic ring or may additionally be CR₁₃R₁₄ when part of a non aromatic ring;

R₁₁, R₁₃ and R₁₄ are at each occurrence independently selected from: H; (C₁₋₄)alkylthio; halo; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; hydroxy(C₁₋₄)alkyl; mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; trifluoromethoxy; nitro; cyano; carboxy; amino or aminocarbonyl unsubstituted or substituted by (C₁₋₄)alkyl;

R₁₂ is at each occurrence independently hydrogen; trifluoromethyl; (C₁₋₄)alkyl unsubstituted or substituted by hydroxy, carboxy, (C₁₋₄)alkoxy, (C₁₋₆)alkylthio, halo or trifluoromethyl; (C₂₋₄)alkenyl; or aminocarbonyl wherein the amino group is optionally substituted with (C₁₋₄)alkyl; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, this invention provides a compound of formula (I) wherein Z₁ and Z₄ are N; and Z₃ is CR^(1a).

In some embodiments, this invention provides a compound of formula (I) wherein R₁ is OCH₃.

In some embodiments, this invention provides a compound of formula (I) wherein R^(1a) is at each occurrence independently hydrogen; halogen; or cyano.

In some embodiments, this invention provides a compound of formula (I) wherein R₂ is hydrogen.

In some embodiments, this invention provides a compound of formula (I) wherein R₃ and R₄ are each independently selected from hydrogen, hydroxyl, halogen, and (C₁₋₆)alkyl.

In some embodiments, this invention provides a compound of formula (I) wherein R₅ is hydrogen.

In some embodiments, this invention provides a compound of formula (I) wherein B is CH₂.

In some embodiments, this invention provides a compound of formula (I) wherein U is CH₂.

In some embodiments, this invention provides a compound of formula (I) wherein R₁₀ is 4H-Pyrido[3,2-b][1,4]thiazin-3-oxo-6-yl; 4H-Pyrido[3,2-b][1,4]oxazin-3-oxo-6-yl; or 2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl.

In some embodiments, this invention provides a compound of formula (I) wherein Z₁ and Z₄ are N; and Z₃ is CR^(1a); R₁ is OCH₃; R^(1a) is at each occurrence independently hydrogen; halogen; or cyano; R₂ is hydrogen; and R₃ and R₄ are each independently selected from hydrogen, hydroxyl, halogen, and (C₁₋₆)alkyl.

In some embodiments, this invention provides a compound of formula (I) wherein Z₁ and Z₄ are N; and Z₃ is CR^(1a); R₁ is OCH₃; R^(1a) is at each occurrence independently hydrogen; halogen; or cyano; R₂ is hydrogen; R₃ and R₄ are each independently selected from hydrogen, hydroxyl, halogen, and (C₁₋₆)alkyl; R₅ is hydrogen; B is CH₂; and U is CH₂.

In some embodiments, this invention provides a compound of formula (I) wherein Z₁ and Z₄ are N; and Z is CR^(1a); R₁ is OCH₃; R^(1a) is at each occurrence independently hydrogen; halogen; or cyano; R₂ is hydrogen; and R₃ and R₄ are each independently selected from hydrogen, hydroxyl, halogen, and (C₁₋₆)alkyl; R₅ is hydrogen; B is CH₂; U is CH₂; R^(1a) of Z₂, Z₃, and Z₅ is hydrogen; R^(1a) of Z₆ is fluorine; R₃ and R₄ of W₁ and W₂ are hydrogen; R₃ of W₃ is hydrogen; R₄ of W₃ is hydroxy; and R₂ and R₈ are independently hydrogen or (C₁₋₆)alkyl.

In some embodiments, this invention provides a compound of formula (I) wherein Z₁ and Z₄ are N; and Z₃ is CR^(1a); R₁ is OCH₃; R^(1a) is at each occurrence independently hydrogen; halogen; or cyano; R₂ is hydrogen; and R₃ and R₄ are each independently selected from hydrogen, hydroxyl, halogen, and (C₁₋₆)alkyl; R₅ is hydrogen; B is CH₂; U is CH₂; R^(1a) of Z₂, Z₃, and Z₅ is hydrogen; R^(1a) of Z₆ is fluorine; R₃ and R₄ of W₁ and W₂ are hydrogen; R₃ of W₃ is hydrogen; R₄ of W₃ is hydroxy; R₂ and R₈ are independently hydrogen or (C₁₋₆)alkyl; and R₁₀ is 4H-Pyrido[3,2-b][1,4]thiazin-3-oxo-6-yl; 4H-Pyrido[3,2-b][1,4]oxazin-3-oxo-6-yl; or 2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl.

In some embodiments, this invention provides a compound of formula (I) wherein the compound is (3R,4R)—N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide; (3R,4R)—N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide; (3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide; (1S,3R,4R)-3-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide; (1S,3R,4R)-3-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide; or (1S,3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]cyclopentanecarboxamide; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, this invention provides a pharmaceutical composition comprising a compound of formula (I) or any other structural embodiment of the invention, and a pharmaceutically acceptable carrier

In some embodiments, this invention provides a method of treating bacterial infections in mammals which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or any other structural embodiment of the invention.

In some embodiments, this invention describes compounds of formula I wherein the (a) and (b) rings of R₁₁ are both aromatic as demonstrated by the following non-limiting examples: 1H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b]-pyrid-2-yl, 3H-quinazolin-4-one-2-yl, benzimidazol-2-yl, benzo[1,2,3]-thiadiazol-5-yl, benzo[1,2,5]-oxadiazol-5-yl, benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl, benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[1,2-a]pyridin-2-yl, imidazo-[1,2-a]-pyrimidin-2-yl, indol-2-yl, indol-6-yl, isoquinolin-3-yl, [1,8]-naphthyridine-3-yl, oxazolo[4,5-b]-pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, indan-2-yl, naphthalen-2-yl, 1,3-dioxo-isoindol-2-yl, benzimidazol-2-yl, benzothiophen-2-yl, 1H-benzotriazol-5-yl, 1H-indol-5-yl, 3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione-6-yl, 3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2-yl, 3H-quinazolin-4-one-6-yl, 4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl, benzo[1,2,3]thiadiazol-6-yl, benzo[1,2,5]thiadiazol-5-yl, benzo[1,4]oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl, cinnolin-3-yl, imidazo[1,2-a]pyridazin-2-yl, imidazo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyrimidin-6-yl, pyrazolo[5,1-c][1,2,4]triazin-3-yl, pyrido[1,2-a]pyrimdin-4-one-2-yl, pyrido[1,2-a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6-yl, thiazolo[3,2-a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl, thieno[3,2-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-6-yl, 4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl, 1-oxo-1,2-dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl, [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl.

In yet other embodiments, R₁₁ is defined by a non-aromatic (a) ring and aromatic (b) ring as illustrated by the following non-limiting examples: (2S)-2,3-dihydro-1H-indol-2-yl, (2S)-2,3-dihydro-benzo[1,4]dioxine-2-yl, 3-(R,S)-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl, 3-(R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl, 3-(S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl, 2,3-dihydro-benzo[1,4]dioxan-2-yl, 3-substituted-3H-quinazolin-4-one-2-yl, 2,3-dihydro-benzo[1,4]dioxan-2-yl, 1-oxo-1,3,4,5-tetrahydrobenzo[c]azepin-2-yl.

In still other embodiments, R₁₁ is defined by an aromatic (a) ring and a non aromatic (b) ring as illustrated by the following non-limiting examples: 1,1,3-trioxo-1,2,3,4-tetrahydro-1-benzo[1,4]thiazin-6-yl, benzo[1,3]dioxol-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2-oxo-2,3-dihydro-benzooxazol-6-yl, 4H-benzo[1,4]oxazin-3-one-6-yl (3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl), 4H-benzo[1,4]thiazin-3-one-6-yl (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl), 4H-benzo[1,4]oxazin-3-one-7-yl, 4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-yl, 5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl, benzo[1,3]dioxol-5-yl, 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl, 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl, 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl, 2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl, 2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-yl, 3,4-dihydro-2H-benzo[1,4]oxazin-6-yl, 3-substituted-3H-benzooxazol-2-one-6-yl, 3-substituted-3H-benzooxazole-2-thione-6-yl, 3-substituted-3H-benzothiazol-2-one-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl, 3,4-dihydro-2H-benzo[1,4]thiazin-6-yl, 3,4-dihydro-1H-quinolin-2-one-7-yl, 3,4-dihydro-1H-quinoxalin-2-one-7-yl, 6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one-2-yl, 5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl, 2-oxo-3,4-dihydro-1H-[1,8]naphthyridin-6-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.

Unless otherwise defined, the term “alkyl” when used alone or when forming part of other groups (such as the ‘alkoxy’ group) includes substituted or unsubstituted, straight or branched chain alkyl groups containing the specified range of carbon atoms. For example, the term “(C₁₋₆)alkyl” include methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, tert-butyl, iso-pentyl, and the like.

The term “alkenyl” means a substituted or unsubstituted alkyl group of the specified range of carbon atoms, wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond. For example, the term “(C₂₋₆)alkenyl” include ethylene, 1-propene, 2-propene, 1-butene, 2-butene, and isobutene, and the like. Both cis and trans isomers are included.

The term “cycloalkyl” refers to substituted or unsubstituted carbocyclic system of the specified range of carbon atoms, which may contain up to two unsaturated carbon-carbon bonds. For example, the term “(C₃₋₇)cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl.

The term “alkoxy” refers to an O-alkyl radical where the alkyl group contains the specified range of carbon atoms and is as defined herein.

The term “acyl” refers to a C(═O)alkyl or a C(═O)aryl radical. In some embodiments, the alkyl group contains 13 or less carbons; in some embodiments 10 or less carbon atoms; in some embodiments 6 or less carbon atoms; and is as otherwise defined. Aryl is as defined herein.

The term “alkylcarbonyl” refers to a (C₁₋₆)alkyl(C═O)(C₁₋₆)alkyl group wherein alkyl is as otherwise defined herein.

The term “alkylsulphonyl” refers to a SO₂alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.

The term “alkylthio” refers to a Salkyl wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.

The term “aminosulphonyl” refers to a SO₂N radical wherein the nitrogen is substituted as specified.

The term “aminocarbonyl” refers to a carboxamide radical wherein the nitrogen of the amide is substituted as defined.

The term “heterocyclylthio” refers to a S-heterocyclyl radical wherein the heterocyclyl moiety is as defined herein.

The term “heterocyclyloxy” refers to an O-heterocyclyl radical wherein heterocyclyl is as defined herein.

The term “arylthio” refers to an S-aryl radical wherein aryl is as defined herein.

The term “aryloxy” refers to an O-aryl radical wherein aryl is as defined herein.

The term “acylthio” refers to a S-acyl radical wherein acyl is as defined herein.

The term “acyloxy” refers to an O-acyl radical wherein acyl is as defined herein.

The term “alkoxycarbonyl” refers to a CO₂alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.

The term “alkenyloxycarbonyl” refers to a CO₂alkyl radical wherein the alkenyl group contains the specified range of carbon atoms and is as defined herein.

The term “alkylsulphonyloxy” refers to an O—SO₂alkyl radical wherein the alkyl group contains the specified range of carbon atoms and is as defined herein.

The term “arylsulphonyl” refers to a SO₂aryl radical wherein aryl is as herein defined.

The term “arylsulphoxide” refers to a SOaryl radical wherein aryl is as defined herein.

Unless otherwise defined, suitable substituents for any alkyl, alkoxy, alkenyl, and cycloalkyl groups includes up to three substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, carboxy, amino, amidino, sulphonamido, unsubstituted (C₁₋₃)alkoxy, trifluromethyl, and acyloxy.

Halo or halogen includes fluoro, chloro, bromo and iodo.

The term “haloalkyl” refers to an alkyl radical containing the specified range of carbon atoms and is as otherwise defined herein, which is further substituted with 1-3 halogen atoms.

The term “haloalkoxy” refers to an alkoxy radical of the specified range and as defined herein, which is further substituted with 1-3 halogen atoms.

The term “hydroxyalkyl” refers to an alkyl group as defined herein, further substituted with a hydroxy group.

Unless otherwise defined, the term “heterocyclic” or “heterocyclyl” as used herein includes optionally substituted aromatic and non-aromatic, single and fused, mono- or bicyclic rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or C-substituted by, for example, up to three groups selected from (C₁₋₄)alkylthio; halo; (C₁₋₄)haloalkoxy; (C₁₋₄)haloalkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; hydroxy, (C₁₋₄)alkyl; (C₁₋₄)thioalkyl; (C₁₋₄)alkoxy; nitro; cyano, carboxy; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonyl wherein the amino group is optionally substituted by (C₁₋₄)alkyl or (C₂₋₄)alkenyl.

Each heterocyclic ring suitably has from 3 to 7, preferably 5 or 6, ring atoms. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.

Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.

Where an amino group forms part of a single or fused non-aromatic heterocyclic ring as defined above suitable optional substituents in such substituted amino groups include hydrogen; trifluoromethyl; (C₁₋₄)alkyl optionally substituted by hydroxy, (C₁₋₄)alkoxy, (C₁₋₄)alkylthio, halo or trifluoromethyl; and (C₂₋₄)alkenyl.

The term “heterocyclylalkyl” refers to a (C₁₋₆)alkyl radical which bears as a substituent a heterocyclyl group, wherein heterocyclyl and alkyl are as herein defined. The heterocyclyl group may be joined to a primary, secondary or tertiary carbon of the (C₁₋₆)alkyl chain.

When used herein the term “aryl”, includes optionally substituted phenyl and naphthyl.

Aryl groups may be optionally substituted with up to five, preferably up to three, groups selected from (C₁₋₄)alkylthio; halo; (C₁₋₄)haloalkoxy; (C₁₋₄)haloalkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; (C₁₋₄)hydroxyalkyl; (C₁₋₄)alkylthio; (C₁₋₄)alkoxy; nitro; cyano; carboxy; amino or aminocarbonyl optionally substituted by (C₁₋₄)alkyl; (C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl.

The term “aralkyl” refers to a (C₁₋₆)alkyl radical which bears as a substituent an aryl group, wherein aryl and alkyl are as herein defined. The aryl group may be joined to a primary, secondary or tertiary carbon of the (C₁₋₆)alkyl chain.

This invention also contemplates that some of its structural embodiments may be present as a solvate. Solvates may be produced from crystallization from a given solvent or mixture of solvents, inorganic or organic. Solvates may also be produced upon contact or exposure to solvent vapors, such as water. This invention includes within its scope stoichiometric and non-stoichiometric solvates including hydrates.

Furthermore, it will be understood that phrases such as “a compound of Formula I or a pharmaceutically acceptable salt, solvate or derivative thereof” are intended to encompass the compound of Formula I, a derivative of formula (I), a pharmaceutically acceptable salt of the compound of formula (I), a solvate of formula (I), or any pharmaceutically acceptable combination of these. Thus by way of non-limiting example used here for illustrative purpose, “a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof” may include a pharmaceutically acceptable salt of a compound of formula (I) that is further present as a solvate.

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the formula (I) or pharmaceutically acceptable derivative thereof.

Pharmaceutically acceptable salts of the above-mentioned compounds of formula (I) include the free base form or their acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids. Compounds of formula (I) may also be prepared as the N-oxide. Compounds of formula (I) having a free carboxy group may also be prepared as an in vivo hydrolysable ester. The invention extends to all such derivatives. One of skill in the art will recognize that where compounds of the invention contain multiple basic sites, a compound of the invention may be present as a salt complexed with more than one equivalent of a corresponding acid or mixture of acids.

Pharmaceutically acceptable derivatives refers to compounds of formula (I) that have been covalently modified with a group that undergoes at least some in vivo cleavage to a compound of formula (I).

Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester-forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt.

Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):

wherein R^(a) is hydrogen, (C₁₋₆) alkyl, (C³⁻⁷) cycloalkyl, methyl, or phenyl, R^(b) is (C₁₋₆) alkyl, (C₁₋₆)alkoxy, phenyl, benzyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyloxy, (C₁₋₆)alkyl(C₃₋₇) cycloalkyl, 1-amino(C₁₋₆)alkyl, or

1-(C₁₋₆ alkyl)amino(C₁₋₆)alkyl; or R^(a) and R^(b) together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R^(c) represents (C₁₋₆)alkylene optionally substituted with a methyl or ethyl group and R^(d) and R^(e) independently represent (C₁₋₆)alkyl; R^(f) represents (C₁₋₆)alkyl; R^(g) represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C₁₋₆)alkyl, or (C₁₋₆)alkoxy; Q is oxygen or NH; R^(h) is hydrogen or

(C₁₋₆)alkyl; R^(j) is hydrogen, (C₁₋₆)alkyl optionally substituted by halogen, (C₂₋₆)alkenyl, (C₁₋₆)alkoxycarbonyl, aryl or heteroaryl; or R^(h) and R^(i) together form (C₁₋₆) alkylene; R^(j) represents hydrogen, (C₁₋₆) alkyl or (C₁₋₆)alkoxycarbonyl; and R^(k) represents (C₁₋₈)alkyl, (C₁₋₈)alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkoxy or aryl.

Examples of suitable in vivo hydrolysable ester groups include, for example, acyloxy(C₁₋₆)alkyl groups such as acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl; (C₁₋₆)alkoxycarbonyloxy(C₁₋₆)alkyl groups, such as ethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; di(C₁₋₆)alkylamino(C₁₋₆)alkyl especially di(C₁₋₄)alkylamino(C₁₋₄)alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(C₁₋₆)alkoxycarbonyl)-2-(C₂₋₆)alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl.

A further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula:

wherein R^(k) is hydrogen, C₁₋₆alkyl or phenyl.

R is preferably hydrogen.

Compounds of formula (I) may also be prepared as the corresponding N-oxides.

Certain of the compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such form, including pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

One of skill in the readily appreciates that optimization for a given reaction may require some routine variation in reaction parameters such as reaction time, temperature, energy source, pressure, light, pressure, solvent or solvents used, co-reagents, catalysts, and the like.

Protective groups wherever found herein may be designated by their specific formula or alternatively, may be referred to generically by P or P_(n) (wherein n is an integer). It is to be appreciated that where generic descriptors are used, that such descriptors are at each occurrence independent from each other. Thus, a compound with more than one of the same generic descriptors (e.g. P) does not indicate that each P is the same protective group, they may be the same or different, so long as the group is suitable to the chemistry being employed. Where protection or deprotection is generically referred to, one of ordinary skill in the art will understand this to mean that suitable conditions are employed that will allow for the removal of the protecting group to be removed while minimizing reaction at other positions of the molecule, unless otherwise indicated. Many protective groups and protective group strategies are known to those of skill in the art in may be found in numerous references including, Greene, et al. “Protective Groups in Organic Synthesis” (Published by Wiley-Interscience), which is herein incorporated by reference in its entirety.

Leaving groups wherever found herein may be designated by a specific chemical formula, or alternatively, may be generically referred to as L or Ln (wherein n is an integer). It is to be appreciated that where a generic descriptor is used, that such descriptors are at each occurrence independent from each other. Leaving groups can be single atoms such as Cl, Br, or I, or may be a group such as OSO₂CH₃, OC(═O)CH₃, O(C═O)CF₃, OSO₂CF₃, and the like. Leaving groups may be formed during the course of a reaction and thus a compound containing a leaving group may not always be an isolated material but rather as a reactive intermediate. By way of non-limiting example, a carboxylic acid may be reacted with a coupling reagent such as DCC, CDl, EDCl, isobutyl chloroformate, etc, and the corresponding reactive intermediate thus formed is further reacted with the nucleophilic coupling partner. In such cases, one of skill in the art appreciates that the activation step may be performed before the introduction of the nucleophilic coupling partner, or in some cases, even in the presence of the nucleophilic coupling partner (depending upon the identity of the particular activating agent, carboxylic acid and nucleophilic coupling partner used). One skilled in the art readily ascertains that leaving groups generally refer to atoms or groups which can be eliminated, substituted or otherwise dissociate during the course of the reaction.

The antibacterial compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibacterials.

The pharmaceutical compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.

The composition may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

The compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibacterials. If the other antibacterial is a β-lactam then a β-lactamase inhibitor may also be employed.

Compounds of formula (I) are active against a wide range of organisms including both Gram-negative and Gram-positive organisms.

The compounds of this invention may also be used in the manufacture of medicaments useful in treating bacterial infections in humans or other mammals.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference (whether specifically stated to be so or not) as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form, for example, of product, composition, process, or use claims.

The following examples illustrate the preparation of certain compounds of formula (I) and the activity of certain compounds of formula (I) against various bacterial organisms. Although specific examples are described in the schemes, one of skill in the art appreciates that the methods are more generally applicable.

One of skill in the art readily appreciates that although the following schemes describe specific examples, they may be more generally applied to produce additional embodiments of this invention. Furthermore, the examples set forth below are illustrative of the present invention and are not intended to limit, in any way, the scope of the present invention.

The compounds of the present invention were prepared by the methods illustrated in Schemes I and II.

Carboxylic acid I-1 was reacted with isobutylene and sulfuric acid to give ester I-2. The unsaturated ester I-2 was heated with a hydroxylamine and paraformaldehyde to give cycloaddition product I-3. Hydrogenation of I-3 cleaved the N—O bond and concommitantly removed the benzyl functionality yielding amino alcohol I-4. Protection of the primary amine with a benzyl carbamate followed by hydrolysis of the ester with TFA provided acid I-6. The use of protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes, such as Greene, “Protective Groups in Organic Synthesis” (published by Wiley-Interscience). Conversion of the carboxylic acid functionality to primary amide I-7 was achieved with Boc anhydride and NH₄HCO₃. The amide was then coupled to the aryl bromide or triflate using standard Buchwald coupling conditions. Removal of the benzyl carbamate was accomplished using Pd/C and hydrogen gas in methanol. The free amine is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH₂Cl₂, EtOH or CH₃CN. The imine was subsequently or simultaneously reacted with a suitable reducing agent such as NaBH₄, NaBH(OAc)₃ or NaBH₃CN in solvent to give the secondary amine I-9. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et₃N), diisopropylethylamine ((i-Pr)₂NEt), or K₂CO₃, mnay be used. Many additional methods for reductive aminations are known, and can be found in standard reference books, such as “Compendium of Organic Synthetic Methods”, Vol. I-VI (published by Wiley-Interscience).

Carboxylic acid I-1 was esterified with methanol and sulfuric acid to give ester II-1. The unsaturated ester II-1 was heated with a hydroxylamine and paraformaldehyde to give cycloaddition product II-2. Conversion of the ester functionality to primary amide II-3 was achieved with ammonia in methanol using a sealed system. The amide was then coupled to an aryl bromide or triflate using standard Buchwald coupling conditions to give amide II-4. Hydrogenation of II-4 results in cleavage of the N—O bond and concommitant removal of the benzyl functionality. Protection of the primary amine with was achieved using a benzyl carbamate affording I-8. The use of protecting groups to mask reactive functionality is well-known to those of skill in the art, and other protecting groups are listed in standard reference volumes, such as Greene, “Protective Groups in Organic Synthesis” (published by Wiley-Interscience). Removal of the benzyl carbamate was accomplished using Pd/C and hydrogen gas in methanol. The free amine is converted to an imine by reaction with an aldehyde in protic or aprotic solvents such as DMF, CH₂Cl₂, EtOH or CH₃CN. The imine is subsequently or simultaneously reacted with a suitable reducing agent such as NaBH₄, NaBH(OAc)₃ or NaBH₃CN in solvent to give the secondary amine I-9. Depending on whether acid neutralization is required, an added base, such as triethylamine (Et₃N), diisopropylethylamine ((i-Pr)₂NEt), or K₂CO₃, may be used. Many additional methods for reductive aminations are known, and can be found in standard reference books, such as “Compendium of Organic Synthetic Methods”, Vol. I-VI (published by Wiley-Interscience).

General

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded at 300 MHz, and chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane (TMS). Abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad. J indicates the NMR coupling constant measured in Hertz. CDCl₃ is deuteriochloroform, DMSO-d₆ is hexadeuteriodimethylsulfoxide, and CD₃OD is tetradeuteriomethanol. Mass spectra were obtained using electrospray (ES) ionization techniques. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, N.J. Melting points were obtained on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius. E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical HPLC was performed on Beckman chromatography systems. Preparative HPLC was performed using Gilson chromatography systems. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nev. Celite® is a filter aid composed of acid-washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colo.

Stereochemical designations in the Examples are relative only.

Preparation 1

Preparation of 4-Bromo-3-fluoro-6-methoxy-[1,5]naphthyridine a) (2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester

A solution of 5-amino-2-methoxypyridine (Aldrich, 100 g, 0.806 mole) and diethyl ethoxymethylenemalonate (Aldrich, 163 mL, 0.806 mole) in EtOH (1 L) was heated at reflux for 4 hours, then was cooled to RT. Concentration to dryness gave the title compound (238 g, quantitative).

b) 6-Methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester

b) Dowtherm A (Fluka, 500 mL) was brought to boiling (250° C.) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distill over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72 g, 73%).

c) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester

A suspension of 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT—may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).

d) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid

2 N NaOH (300 mL, 600 mmole) was added dropwise over 30 min to a stirred solution of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (83.56 g, 268 mmole) in THF (835 mL). Stirring was continued overnight, at which time LC/MS showed that the saponification was complete. 2 N HCl was added to pH 6 and the THF was removed in vacuo. 2 N HCl was added to pH 2, then water (250 mL) was added, and the mixture was cooled thoroughly in ice. The solid was collected by suction filtration, washed with water and dried (first using a rotary evaporator at 50° C. and then under high vacuum at 50° C. overnight) to give the title compound (76.7 g, slightly over quantitative). This material was used without further purification.

e) 4-Bromo-6-methoxy-[1,5]naphthyridin-3-ylamine

A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid (50 g, 177 mmole) in dry DMF (600 mL) was treated with triethylamine (222.5 mL, 1.60 mole), tert-butanol (265 mL, 2.77 mole), and diphenylphosphoryl azide (41.75 mL, 194 mmole). The reaction was stirred under argon at 100° C. for 1 hr, then was cooled to RT and concentrated to low volume. Ethyl acetate and excess aqueous sodium bicarbonate solution were added, the mixture was shaken, and some insoluble solid was filtered off. The layers were separated and the organic phase was washed with water (2×) and dried (MgSO₄). Concentration to dryness gave a crude mixture of 4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (minor product) and (4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine)carbamic acid tert-butyl ester (major product) along with impurities.

Without further purification, this mixture was dissolved in CH₂Cl₂ (150 mL) and treated with trifluoroacetic acid (100 mL). The reaction was stirred for 3 hr then was concentrated to dryness. The residue was partitioned between CHCl₃ and saturated sodium bicarbonate solution and the layers were separated. The aqueous phase was extracted with CHCl₃, and the combined organics were dried (MgSO₄) and concentrated to low volume. The solid was collected by suction filtration, washed with a small volume of CHCl₃ and dried under vacuum to afford a first crop of the title compound (31.14 g). The filtrate was purified by flash chromatography on silica gel (30% EtOAc/CHCl₃) to afford further material (2.93 g, total=34.07 g, 76%). Alternatively, the filtrate was left at RT overnight and then filtered to give a second crop of the title compound (2.5 g).

f) 4-Bromo-6-Methoxy-[1,5]naphthyridine-3-diazonium tetrafluoroborate

A solution of 4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (25.2 g, 99.2 mmole) in dry THF (400 mL) was maintained at −5° C. while nitrosonium tetrafluoroborate (12.9 g, 110 mmole) was added portionwise over 30 min (approximately 2 g portions). The reaction was continued for an additional 1 hr at −5° C., at which time TLC* and LC/MS indicated that the reaction was complete. The orange solid was collected by suction filtration, washed with ice-cold THF and dried under vacuum to provide the title compound (31.42 g, 90%).

g) 4-Bromo-3-fluoro-6-methoxy-[1,5]naphthyridine

A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-diazonium tetrafluoroborate (31.42 g, 89.0 mmole) in decalin (mixed isomers, 500 mL) in a 2 L flask* was heated to 180° C. and held at this temperature for 5 min. The mixture was cooled and diluted with CHCl₃ (500 mL, to keep the product in solution), and the resulting mixture was stirred vigorously for 30 min to break up a black solid byproduct. The mixture was then poured onto a column of silica gel and the column was eluted with CHCl₃ to remove decalin and then with 3% EtOAc/CHCl₃ to afford the title compound (9.16 g, 40%).

Preparation 2

Preparation of 6-(Methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate a) 4-Hydroxy-6-methoxy-[1,5]-naphthyridine

5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000 m) with methyl propiolate (40 ml, 0.44 mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6 g, 48%).

The unsaturated ester (10.5 g, 0.05 mol) in warm Dowtherm A (50 ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26 g, 70%).

b) 6-(Methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate

4-Hydroxy-6-methoxy-[1,5]-naphthyridine (10 g, 0.057 mol) in dichloromethane (200 ml) containing 2,6-lutidine (9.94 ml, 0.086 mol) and 4-dimethylaminopyridine (0.07 g, 0.0057 mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5 ml, 0.063 mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane).

Preparation 3

Preparation of 3-Oxo-3,4-dihydro-2H-pyrido[312-b][1,4]oxazine-6-carboxaldehyde a) 2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0° C. for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification.

MS (ES) m/z219.0 (M+H)⁺.

b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate

2-Bromo-5-hydroxy-6-nitropyridine (30 g, 0.14 mole) was suspended in acetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was added, followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction was heated at reflux for 10 hr, then was cooled to room temperature and diluted with Et₂O. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford material (38 g, 89%), which was used without further purification; MS (ES) m/z 305.0 (M+H)⁺.

c) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one

Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90° C. for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%); MS (ES) m/z229.0 (M+H)⁺.

d) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.0 g, 26.3 mmole) and trans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in 1,4-dioxane (150 mL) and the solution was degassed with argon. (Ph₃P)₄Pd (230 mg, 0.2 mmole) was added, followed by a solution of potassium carbonate (6.9 g, 50 mmole) in H₂O (20 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with EtOAc (200 mL). The solution was washed sequentially with H₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The solid residue was purified by flash chromatography on silica gel (5-10% EtOAc/CHCl₃) to afford a solid (2.5 g, 38%).

MS (ES) m/z253.0 (M+H)⁺.

e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

6-((E)-styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.2 g, 4.8 mmole) was dissolved in CH₂Cl₂ (200 mL) and the solution was cooled to −78° C. Ozone was bubbled through the solution with stirring until a pale blue color appeared, then the excess ozone was removed by bubbling oxygen through the solution for 15 min. Dimethylsulfide (1.76 mL, 24 mmole) was added to the solution, and the reaction was stirred at −78° C. for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et₂O (50 mL). The collected solid was washed with additional Et₂O and dried to afford a solid (700 mg, 82%).

MS (ES) m/z 179.0 (M+H)⁺.

Preparation 4

Preparation of 2,3-Dihydro-[1,4]dioxino[2,3-C]pyridine-7-carboxaldehyde a) 5-Benzyloxy-2-hydroxymethyl-1H-pyridin-4-one

A mixture of 5-benzyloxy-2-hydroxymethyl-4-pyrone (prepared from Kojic acid by the method of D. Erol, J. Med. Chem., 1994, 29, 893) (9.7 g, 40 mmol), concentrated aqueous (880) ammonia (100 mL), and ethanol (20 mL) was heated to reflux overnight. The mixture was allowed to cool to room temperature then filtered. The resultant solid was washed with ether and dried in vacuo (5.9 g); MS (APCI+) m/z 232 (MH+).

b) (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol

A solution of 5-Benzyloxy-2-hydroxymethyl-1H-pyridin-4-one (2 g, 8.7 mmol) in water (220 mL) containing sodium hydroxide (17 mmol) was hydrogenated over 10% palladium on charcoal (1 g) for 4 hours. The mixture was filtered and evaporated to give a white solid. This solid was dissolved in N,N-dimethylformamide (8 mL) then treated with potassium carbonate (2.9 g) and 1,2-dibromoethane (0.6 mL, 7 mmol). The mixture was heated at 85° C. overnight. The cooled mixture was evaporated onto silica and chromatographed eluting with 10-30% methanol in ethyl acetate affording a white solid (250 mg, 21%); MS (APCl+) m/z 168 (MH+).

c) 2,3-Dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde

A solution of (2,3-Dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-methanol (250 mg, 1.5 mmol) in dichloromethane (5 mL) was treated with manganese dioxide (650 mg, 7.5 mmol). After 3 days the mixture was filtered and evaporated affording a white solid (150 mg, 61%); MS (APCI+) m/z 166 (MH+).

Preparation 5

Preparation of 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde a) Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of ethyl 2-mercaptoacetate (1.473 mL) in DMF (48 mL) was ice-cooled and treated with sodium hydride (540 mg of a 60% dispersion in oil). After 1 hour methyl 6-amino-5-bromopyridine-2-carboxylate (3 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 hours at room temperature. The solution was diluted with EtOAc (1 litre), washed with water (3×300 mL), dried and evaporated to about 10 mL. The white solid was filtered off and washed with a little EtOAc to give the ester (0.95 g); MS (APCl⁻) m/z223 ([M—H]⁻, 100%).

b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid

A solution of Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (788 mg) in dioxan (120 ml)/water (30 mL) was treated dropwise over 2 hours with 0.5 M NaOH solution (8 mL) and stirred overnight. After evaporation to approx. 3 ml, water (5 mL) was added and 2 M HCl to pH4. The precipitated solid was filtered off, washed with a small volume of water and dried under vacuum to give a solid (636 mg); MS (APCl⁻) m/z 209 ([M—H]⁻, 5%), 165 ([M—COOH]⁻, 100%).

c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

A solution of 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (500 mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to −10° C. and isobutyl chloroformate (0.339 ml) added. After 20 minutes the suspension was filtered through kieselguhr into an ice-cooled solution of sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30 minutes and the pH reduced to 7 with dilute HCl. The solvent was evaporated and the residue triturated under water. The product was filtered and dried under vacuum to give a white solid (346 mg); MS (APCl⁻) m/z 195 ([M—H]⁻, 50%), 165 (100%).

d) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (330 mg) in dichloromethane (30 mL)/THF (30 mL) was treated with manganese dioxide (730 mg) and stirred at room temperature. Further manganese dioxide was added after 1 hour (730 mg) and 16 hours (300 mg). After a total of 20 hours the mixture was filtered through kieselguhr and the filtrate evaporated. The product was triturated with EtOAc/hexane (1:1) and collected to give a solid (180 mg); MS (APCl⁻) m/z 195 ([M—H]⁻, 95%), 165 (100%).

Preparation 6

Preparation of (±)-phenylmethyl {[(1R,2R,4S)-4-(aminocarbonyl)-2-hydroxycyclopentyl]methyl}carbamate a) (±)-1,1-dimethylethyl (3aR,5S,6aR)-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxylate

To a solution of 1,1-dimethylethyl 3-cyclopentene-1-carboxylate (8.4 g, 50.0 mmole) [JACS, 1983, 105, 2435-2439] in toluene (150 mL) and EtOH (75 mL) was added paraformaldehyde (11.0 g, 250 mmole), N-hydroxybenzylamine hydrochloride (11.8 g, 75 mmole) and triethylamine (10.4 mL, 75 mmole). After 24 hours at 80° C., the reaction solution was concentrated under vacuum and redissolved in hexanes/EtOAc, 4:1 (200 mL) and filtered. The organic solution was concentrated and then purified on silica (hexanes/EtOAc, 4:1) to give the title compound (13.0 g, 86%) as a light yellow oil: LC-MS (ES) m/e 304 (M+H)⁺.

b) (±)-1,1-Dimethylethyl(1S,3R,4R)-3-(aminomethyl)-4-hydroxycyclopentanecarboxylate

To a solution of (±)-1,1-dimethylethyl (3aR,5S,6aR)-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxylate (13.0 g, 42.9 mmole) in EtOH (100 mL) in a Parr flask was added Pd(OH)₂ (˜400 mg). The reaction contents were shaken under 50 psi of H₂ overnight at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (7.87, 99%) as a white solid: LC-MS (ES) m/e 216 (M+H)⁺.

c) (±)-1,1-dimethylethyl(1S,3R,4R)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]cyclopentanecarboxylate

To a solution of (±)-1,1-dimethylethyl (1S,3R,4R)-3-(aminomethyl)-4-hydroxycyclopentanecarboxylate (7.9 g, 37.0 mmole) in DCM (100 mL) at RT was added Et₃N (6.7 mL, 48.4 mmole) and N-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.4 mmole). After 18 h, the DCM was removed under vacuum and the residue purified on silica (1:1, hexanes/EtOAc) to give the title compound (11.6 g, 89%) as a white solid: LC-MS (ES) m/e 350 (M+H)⁺.

d) (±)-phenylmethyl {[(1R,2R,4S)-4-(Aminocarbonyl)-2-hydroxycyclopentyl]methyl}carbamate

To a solution of (±)-1,1-dimethylethyl (1S,3R,4R)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]cyclopentanecarboxylate (11.4 g, 32.7 mmole) in DCM (75 mL) was added HCl (50 mL, 4M in dioxane). After stirring 6 h at RT, the reaction solution was concentrated under vacuum to give a white solid: LC-MS (ES) m/e 294 (M+H)⁺.

To the solid in THF (100 mL) at RT was added pyridine (2.1 mL, 25.6 mmole) and NH₄HCO₃ (6.8 g, 85.3 mmole). Di-tert-butyl dicarbonate (4.84 g, 22.2 mmole) was then added to the solution with continued stirring for 5 hours. The reaction solution was filtered and concentrated under vacuum. The residue was purified on silica [MeOH (w/5% NH₄OH)/CHCl₃, 1:9] to afford the title compound (3.0 g, 60%) as a white solid: LC-MS (ES) m/e 293 (M+H)⁺.

Preparation 7 Preparation of (±)-(1S,3R,4R)-3-(aminomethyl)-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide

a) (±)-methyl (3aR,5S,6aR)-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxylate

To a solution of methyl-3-cyclopentene-1-carboxylate (6.1 g, 48.4 mmole) in toluene (150 mL) and EtOH (75 mL) was added paraformaldehyde (10.6 g, 242 mmole), N-hydroxybenzylamine hydrochloride (11.4 g, 72.6 mmole) and triethylamine (10.1 mL, 72.6 mmole). After 24 hours at 80° C., the reaction solution was concentrated under vacuum and redissolved in hexanes/EtOAc, 4:1 (200 mL) and filtered. The organic solution was concentrated and then purified on silica (hexanes/EtOAc, 4:1) to give the title compound (10.7 g, 85%) as a light yellow oil containing mixture of diastereoisomers in the ratio of 6 (trans) to 1 (cis): LC-MS (ES) m/e 262 (M+H)⁺.

The title compound was separated into pure diastereomers via reverse phase HPLC (see below).

b) (±)-(3aR,5S,6aR)-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxamide

To a solution of (±)-trans-methyl (3aR,5S,6aR)-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxylate (10.0 g, 38.2 mmole) in MeOH (10 mL) in a pressure tube was added NH₃ (50 mL, 7M in CH₃OH). The contents were heated to 55° C. for 72 h and then concentrated under vacuum. The residue was purified on silica (CHCl₃/MeOH, 9:1) to afford the title compound (8.77 g, 93%) as a light orange solid: LC-MS (ES) m/e 247 (M+H)⁺.

c) (±)-trans-(3aR,5S,6aR)—N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxamide

To a solution of (±)-(3aR,5S,6aR)-2-(phenylmethyl)hexahydro-2H- cyclopenta[d]isoxazole-5-carboxamide (5.0 g, 20.33 mmole) in dioxane (75 mL) was added rac-BINAP (0.76 g, 1.22 mmole), cesium carbonate (8.28 g, 25.41 mmole), 4-bromo-3-fluoro-6-methoxy-[1,5]naphthyridine (5.20 g, 20.33 mmole) and Pd₂(dba)₃ (0.42 g, 0.41 mmole). After heating to 95° C. for 48 h under N₂, the reaction contents were concentrated in vacuo and purified on silica (CHCl₃/MeOH/NH₄OH, 90:9:1) to give the title compound (4.2 g, 49%) as a tan solid: LC-MS (ES) m/e 423 (M+H)⁺.

d) (±)-trans-phenylmethyl {[(1R,2R,4S)-4-({[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]amino}carbonyl)-2-hydroxycyclopentyl]methyl}carbamate

To a solution of (±)-(3aR,5S,6aR)—N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-(phenylmethyl)hexahydro-2H-cyclopenta[d]isoxazole-5-carboxamide (3.7 g, 8.77 mmole) in MeOH (100 mL) in a Parr flask was added Pd(OH)₂ (˜400 mg). The reaction contents were shaken under 50 psi of H₂ for 72 h at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (2.75, 94%) as a white solid: LC-MS (ES) m/e 335 (M+H)⁺.

To the amine (2.5 g, 7.48 mmole) dissolved in DCM/DMF (100 mL/25 mL) was added N-(benzyloxycarbonyloxy)succinimide (2.42 g, 9.73 mmole) and triethylamine (1.36 mL, 9.73 mmole). After stirring for 24 h at RT, the reaction solution was concentrated and purified on silica (CHCl₃/MeOH/NH₄OH, 90:9:1) to give the title compound (2.5 g, 71%) as an off-white solid: LC-MS (ES) m/e 423 (M+H)⁺.

e) (±)-trans-(1S,3R,4R)-3-(aminomethyl)-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide

To a solution of (±)-phenylmethyl {[(1R,2R,4S)-4-({[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]amino}carbonyl)-2-hydroxycyclopentyl]methyl}carbamate (2.2 g, 4.70 mmole) in MeOH (100 mL) was added Pd(OH)₂ (˜400 mg). The reaction contents were stirred under a balloon of H₂ overnight at RT. The reaction contents were filtered through Celite® (MeOH) and concentrated to give the title compound (1.3 g, 83%) as an off-white solid: LC-MS (ES) m/e 335 (M+H)⁺.

Preparation 8 Preparation of (±)-trans-(1S,3R,4R)-3-(aminomethyl)-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]cyclopentanecarboxamide

Prepared according to the procedure of Preparation 7, except substituting 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate for 4-bromo-3-fluoro-6-methoxy-[1,5]naphthyridine, to give the title compound as an off-white solid: LC-MS (ES) m/e 318 (M+H)⁺.

Example 1 Preparation of (±)-(1S,3R,4R)—N—[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide

To a stirred solution of (±)-(1S,3R,4R)-3-(aminomethyl)-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide (0.43 g, 1.29 mmole) in dry CH₂Cl₂ (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.25 g, 1.29 mmole). After 24 h, at RT was added NaBH(OAc)₃ (0.41 g, 1.93 mmole). After 4 h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl₃/MeOH, 9:1 containing 5% NH₄OH) afforded the title compound (0.12 g, 18%) as light yellow solid: ¹H NMR (400 MHz, d₈-dioxane), δ8.75 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.35 (m, 1H), 4.10 (s, 3H), 3.78 (s, 2H), 3.49 (s, 2H), 3.36 (m, 1H), 2.81 (m, 1H), 2.73 (m, 1H), 2.20 (m, 3H), 2.04 (m, 1H), 1.87 (m, 1H). LC-MS (ES) m/e 513 (M+H)⁺.

Example 2 Preparation of (±)-(1S,3R,4R)—N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxy-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide

According to the procedure of Example 1 except substituting 3-oxo-3,4-dihydro-2H-pyrido[1,4]oxazine-6-carboxaldehyde (0.23 g, 1.29 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde, the title compound (90 mg, 14%) was prepared as an off-white solid: ¹H NMR (400 MHz, CD₃OD), δ 8.90 (s, 1H), 8.30 (d, J=9.1 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 4.71 (s, 2H), 4.48 (m, 1H), 4.29 (s, 2H), 4.16 (s, 3H), 3.60 (m, 1H), 3.47 (m, 1H), 3.21 (m, 1H), 2.50 (m, 1H), 2.27 (m, 3H), 2.03 (m, 1H). LC-MS (ES) m/e 497 (M+H)⁺.

Example 3 Preparation of (±)-(1S,3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide

According to the procedure of Example 1 except substituting 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.21 g, 1.29 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde, the title compound (170 mg, 27%) was prepared as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.70 (m, 1H), 8.21 (d, J=9.0 Hz, 1H), 8.12 (s, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.75 (s, 1H), 4.59 (m, 1H), 4.38 (m, 2H), 4.34 (m, 2H), 4.12 (s, 3H), 3.89 (m, 1H), 3.77 (m, 1H), 3.44 (m, 1H), 2.90 (m, 2H), 2.35 (m, 1H), 2.28 (m, 3H), 1.91 (m, 1H). LC-MS (ES) m/e 484 (M+H)⁺.

Example 4 Preparation of (±)-(1S,3R,4R)-3-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide

To a stirred solution of (±)-(1S,3R,4R)-3-(aminomethyl)-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]cyclopentanecarboxamide (0.48 g, 1.51 mmole) in dry CH₂Cl₂ (50 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.29 g, 1.51 mmole). After 24 h, at RT was added NaBH₄ (0.063 g, 1.66 mmole). After 4 h, the reaction solution was concentrated under vacuum to a solid. Purification on silica (CHCl₃/MeOH, 9:1 containing 5% NH₄OH) afforded the title compound (0.13 g, 17%) as light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 9.44 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.92 (m, 3H), 3.49 (s, 2H), 3.38 (m, 1H), 2.95 (m, 2H), 2.39 (m, 1H), 2.50 (m, 4H), 1.91 (m, 1H). LC-MS (ES) m/e 495 (M+H)⁺.

Example 5 Preparation of (±)-(1S,3R,4R)-3-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]-4-({[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}methyl)cyclopentanecarboxamide

According to the procedure of Example 4 except substituting 3-oxo-3,4-dihydro-2H-pyrido[1,4]oxazine-6-carboxaldehyde (0.27 g, 1.51 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde, the title compound (110 mg, 15%) was prepared as an off-white solid: ¹H NMR (400 MHz, CDCl₃), δ 9.44 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.65 (s, 3H), 4.13 (s, 2H), 3.86 (m, 1H), 3.70 (s, 2H), 2.92 (m, 2H), 2.61 (m, 1H), 2.32 (m, 4H), 2.05 (m, 1H). LC-MS (ES) m/e 479 (M+H)⁺.

Example 6 Preparation of (±)-(1S,3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]Cyclopentanecarboxamide

According to the procedure of Example 4 except substituting 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.25 g, 1.51 mmole) for 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde, the title compound (57 mg, 8%) was prepared as an off-white solid: ¹H NMR (400 MHz, CDCl₃), δ 9.43 (m, 1H), 8.68 (d, J=5.1 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.20 (d, J=9.0 Hz, 1H), 8.11 (s, 1H), 7.16 (d, J=9.1 Hz, 1H), 6.61 (s, 1H), 4.61 (m, 1H), 4.38 (m, 2H), 4.31 (m, 2H), 4.12 (s, 3H), 3.89 (m, 2H), 3.38 (m, 1H), 2.92 (m, 2H), 2.36 (m, 1H), 2.24 (m, 3H), 1.92 (m, 1H). LC-MS (ES) m/e 466 (M+H⁺.

Example Structure Formula 1

(±)-(1S,3R,4R)-N-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]-3- hydroxy-4-({[(3-oxo-3,4-dihydro-2H- pyrido[3,2-b][1,4]thiazin-6- yl)methyl]amino}methyl)cyclopentane carboxamide 2

(±)-(1S,3R,4R)-N-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]-3- hydroxy-4-({[(3-oxo-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-6- yl)methyl]amino}methyl)cyclopentane carboxamide 3

(±)-(1S,3R,4R)-3-{[(2,3- dihydro[1,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-N-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]-4- hydroxycyclopentanecarboxamide 4

(±)-(1S,3R,4R)-3-hydroxy-N-[6- (methyloxy)-1,5-naphthyridin-4-yl]-4- ({[(3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1,4]thiazin-6-yl)methyl]amino} methyl)cyclopentane carboxamide 5

(±)-(1S,3R,4R)-3-hydroxy-N-[6- (methyloxy)-1,5-naphthyridin-4-yl]-4- ({[(3-oxo-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-yl) methyl]amino} methyl)cyclopentane carboxamide 6

(±)-(1S,3R,4R)-3-{[(2,3- dihydro[1,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino]methyl}-4-hydroxy-N- [6-(methyloxy)-1,5-naphthyridin-4- yl]cyclopentanecarboxamide

Example 7 Antimicrobial Activity Assay

Whole-cell antimicrobial activity was determined by broth microdilution using the National Committee for Clinical Laboratory Standards (NCCLS) recommended procedure, Document M7-A6, “Methods for Dilution Susceptibility Tests for Bacteria that Grow Aerobically”. The compounds were tested in serial two-fold dilutions ranging from 0.016 to 16 mcg/mL.

Compounds were evaluated against a panel of Gram-positive organisms, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecalis.

In addition, compounds were evaluated against a panel of Gram-negative strains including Haemophilus influenzae, Moraxella catarrhalis and Escherichia coli.

The minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. A mirror reader was used to assist in determining the MIC endpoint.

One skilled in the art would consider any compound with a MIC of less than 20 mg/mL to be a potential lead compound. For instance, each of the listed Examples (1 to 6), as identified in the present application, had a MIC≦20 mg/ml against at least one of the organisms listed above. 

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein: Z₁, Z₃, and Z₄ are independently N or CR^(1a); Z₂, Z₅, and Z₆ are each CR^(1a); R₁ and R^(1a) are independently at each occurrence hydrogen; cyano; halogen; hydroxy; (C₁₋₆)alkoxy unsubstituted or substituted by (C₁₋₆)alkoxy, hydroxy, amino, piperidyl, guanidino or amidino any of which is unsubstituted or N-substituted by one or two (C₁₋₆)alkyl, acyl, (C₁₋₆)alkylsulphonyl, CONH₂, hydroxy, (C₁₋₆)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluoromethyl; trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio; (C₁₋₆)alkylsulphonyl; (C₁₋₆) alkylsulphoxide; arylsulphonyl; arylsulphoxide; or an amino, piperidyl, guanidino or amidino group unsubstituted or N-substituted by one or two (C₁₋₆)alkyl, acyl or (C₁₋₆)alkylsulphonyl groups; or R₁ and R^(1a) of Z₂ together form ethylenedioxy; W₁, W₂, and W₃ are each CR₃R₄; B is CR₆R₇ or C═O; R₃, R₄, R₆, and R₇ are independently at each occurrence hydrogen; thiol; (C₁₋₆)alkylthio; halogen; trifluoromethyl; azido; (C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenylcarbonyl; (C₂₋₆)alkenyloxycarbonyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; hydroxy; NR^(1b)R^(1b); (C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonyl wherein the amino group is optionally and independently substituted by hydrogen, (C₁₋₆)alkyl, (C₂₋₆)alkenyl or aralkyl; R₅ is hydrogen; halogen; hydroxyl; or (C₁₋₆)alkyl; R₂ and R₈ are independently hydrogen; trifluoromethyl; (C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl; aryl; aralkyl; (C₃₋₈)cycloalkyl; heterocyclyl; or heterocyclylalkyl; R^(1b) and R_(1b) are independently at each occurrence hydrogen; (C₁₋₆)alkyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; or together with the nitrogen to which they are attached form an aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring (wherein said aziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ring are optionally substituted with from 1 to 3 substituents selected from halogen; hydroxy; cyano; nitro; (C₁₋₆)alkyl; and aryl); R₉ is UR₁₀, U is OH₂; C(═O); or SO₂; R₁₀ is a group:

R₁₁, R₁₃ and R₁₄ are at each occurrence independently selected from: H; (C₁₋₄)alkylthio; halo; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; hydroxy(C₁₋₄)alkyl; mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; trifluoromethoxy; nitro; cyano; carboxy; amino; and aminocarbonyl: wherein said amino and amino carbonyl may be unsubstituted or substituted by (C₁₋₄)alkyl; and “acyl” is a C(═O)(C₁₋₁₃)alkyl or a C(═O)aryl radical, in which aryl is optionally substituted phenyl or naphthyl.
 2. A compound according to claim 1, wherein Z₁ and Z₄ are N; and Z₃ is CR^(1a).
 3. A compound according to claim 1, wherein: R₁ is OCH₃.
 4. A compound according to claim 1, wherein R^(1a) is at each occurrence independently hydrogen; halogen; or cyano.
 5. A compound according to claim 1, wherein: R₂ is hydrogen.
 6. A compound according to claim 1, wherein: R₃ and R₄ are each independently selected from hydrogen, hydroxy, halogen, and (C₁₋₆)alkyl.
 7. A compound according to claim 1, wherein: R₅ is hydrogen.
 8. A compound according to claim 1, wherein: B is CH₂.
 9. A compound according to claim 1, wherein: U is CH₂.
 10. A compound according to claim 1, wherein R₁₀ is 2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl.
 11. A compound according to claim 2, wherein: R₁ is OCH₃; R^(1a) is at each occurrence independently hydrogen; halogen; or cyano; R₂ is hydrogen; and R₃ and R₄ are each independently selected from hydrogen, hydroxy, halogen, and (C₁₋₆)alkyl.
 12. A compound according to claim 11, wherein: R₅ is hydrogen; B is OH₂; and U is OH₂.
 13. A compound according to claim 2, wherein: R₁ is OCH₃; R^(1a) of Z₂, Z₃, and Z₅ is hydrogen; R^(1a) of Z₆ is fluorine; R₃ and R₄ of W₁ and W₂ are hydrogen; R₃ of W₃ is hydrogen and R₄ of W₃ is hydroxy; R₂ and R₈ are independently hydrogen or (C₁₋₆)alkyl; R₅ is hydrogen; B is CH₂; and U is CH₂.
 14. A compound according to claim 13, wherein R₁₀ is 2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl.
 15. A compound according to claim 1, wherein the compound is: (3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide; (1S,3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]cyclopentanecarboxamide; a pharmaceutically acceptable salt of (3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-N-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-4-hydroxycyclopentanecarboxamide; or a pharmaceutically acceptable salt of (1S,3R,4R)-3-{[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]methyl}-4-hydroxy-N-[6-(methyloxy)-1,5-naphthyridin-4-yl]cyclopentanecarboxamide.
 16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
 17. A method of treating a bacterial infection in a mammal due to Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalls, Haemophilus influenzae, Moraxella catarrhalis or Escherichia coli, which comprises administering to a mammal in need thereof an effective amount of a compound according to claim
 1. 18. A pharmaceutical composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier.
 19. A pharmaceutical composition comprising a compound according to claim 13 and a pharmaceutically acceptable carrier.
 20. A pharmaceutical composition comprising a compound according to claim 15 and a pharmaceutically acceptable carrier.
 21. A method of treating a bacterial infection in a mammal due to Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Haemophllus influenzae, Moraxella catarrhalis or Escherichia coli, which comprises administering to a mammal in need thereof an effective amount of a compound according to claim
 15. 